HCV-specific CD4+ proliferative responses have been repeatedly shown to be the sine qua non condition of viral clearance in acute HCV infection. While this highlights the critical importance of CD4+ T-help in the control of HCV, several urging questions remain to be answered. We still lack a comprehensive analysis of the individual HCV-specific CD4 epitopes targeted and their HLA association, which is essential information in order to understand whether certain responses are associated with a better outcome, but also to facilitate the generation of class II tetramers and functional studies on the single epitope level. Especially class II tetramer studies are required to solve what is possibly the most important question in HCV infection: Whether HCV-specific CD4+ T-cells are absent in those developing chronic infection or whether T-helper cells are present in all individuals during acute infection, but for reasons to be determined fail to proliferate and function in the majority of subjects. We have unique collaborations in place providing us with longitudinal research samples from patients with acute HCV infection and different routes of transmission, different clinical presentations and different outcomes of infection. At the same we have developed methods allowing us to define the HCV-specific CD4 response on the single epitope level in these subjects and to develop class II tetramers for direct visualization of T-helper cells and their functional and phenotypic analysis. We hypothesize that distinctions in the specificities targeted and in the dynamics of T-cell function and phenotype are leading to different outcomes of infection. Determination of the nature of the CD4+ T-cell response associated with viral control will be an important contribution to the development of HCV vaccines and immunotherapies.